Hemorrhagic conditions are diverse in classification, and their pathogenic factors are complicated, including such as abnormality in the structure of vascular walls or connective tissues, abnormality in the amount or function of platelets, abnormality in coagulant factors, over-fibrinolysis, and circulating anti-coagulant substances. Based on the involvement of inheritance, hemorrhagic conditions can be divided into inherited and non-inherited hemorrhagic conditions. Inherited hemorrhagic conditions, such as hemophilia, are resulted from mutations in the coagulant factors, which result in the loss or decrease of coagulation ability. Clinically, most hemorrhagic conditions are non-inherited hemorrhagic conditions, including internal and external traumatic hemorrhage, hemorrhage resulted from insufficient ingestion of nutrition or vitamin K, hemorrhage resulted from gastric or intestinal ulcer, hemorrhage resulted from infectious diseases, hemorrhage resulted from medical behaviors, intrapartum hemorrhage, abnormality in the hematopoietic system, disorders in liver functions, hemorrhage resulted from autoimmune diseases, dengue hemorrhagic fever, hemorrhagic venom attack, anthrax, bacteremia, and hemorrhage resulted from cancer.
Except for traumatic hemorrhage, the present medical treatments have no effect on systemic hemorrhea. The presently known coagulant drugs (such as anti-fibrinolysis agents) are only suitable for treating local hemorrhage. Such coagulant drugs form small thrombus in vivo quickly, and thus often result in side effects such as myocardial infarction and cerebral stroke. Therefore, there exists no suitable and safe systemic haemostatic drugs without side effects.
P-selectin is a member of the selectin family localized in the membranes of α-granules of platelets and the Weibel-Palade bodies (WP bodies) of endothelial cells. Endothelial cells quickly express P-selectin when stimulated by thrombin or histamine. A soluble form of P-selectin (soluble P-selectin; sP-selectin) can be found in the plasma as a circulating protein. A soluble P-selectin molecule, which exists as a monomer in the blood, is 3 kDa smaller than a P-selectin molecule, which exists as an oligomer on a membrane. The soluble P-selectin of healthy individuals originates from the alternatively spliced form found in endothelial cells and platelets (Johnston, G. I. et al., 1990, J. Biol. Chem. 265, 21381-21385).
A previous study showed that the plasma level of soluble P-selectin can be viewed as a useful tool for anticipating thrombotic consumptive platelet disorders (Smith, A. et al., 1999, Throm. Haemost. 82, 1593-1599). Blann, A. D. and Lip, G. Y. indicated that the biological functions of the soluble P-selectin circulating in the blood are unclear (J. Clin. Endocrinol. Metab. (2000) 85, 1745-1747). A Follow-up study utilizing a test determining the plasma clotting time found that soluble P-selectin injected into mice can promote coagulation (Patrick Andre et al., 2000, PNAS Vol. 97, No. 25, 13835-13840). Said study only described the molecular mechanism and local hemorrhage, and inferred that soluble P-selectin may relate to coagulation disorders. However, said study did not indicate that soluble P-selectin can be used in the treatment of systemic hemorrhagic conditions.
Further studies indicated that the plasma soluble P-selectin level of patients suffering from acute myocardial infarction (AMI) and unstable angina pectoris increases significantly (Meral Kayikcioglu et al., Int. J. Cardiol., 2001, 79: 223; Enver Atalar et al., Int. J. Cardiol., 2001, 78: 69). However, said literatures did not suggest anything regarding the treatment of systemic hemorrhagic conditions, either.
In view of the above, no literature disclosed or even suggested the novel use of P-selectin in the treatment of systemic hemorrhagic conditions.